Rôle du métabolisme dans le vieillissement et les maladies liées à l’âge / Role of metabolism in ageing and ageing-related diseases

Séminaire organisé par Linda Partridge (Max Planck Institute for Biology of Ageing, Germany and University College London, UK) et Anne Brunet (Stanford University School of Medicine, USA) du 15 au 20 juin 2015

Participants

Hugo Aguilaniu, Dario Alessi, Rolf Bodmer, Anne Brunet, Jens C. Brüning, Andrew G. Dillin, Michael N. Hall, Malene Hansen, Stella Hurtley, Heinrich Jasper, Brian K. Kennedy, Cynthia J. Kenyon, William Mair, Linda Partridge, J. Andrew Pospisilik, Thomas Rando, Akhilesh B. Reddy, David M. Sabatini, P. Eline Slagboom.

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Résumé

Ce séminaire a rassemblé des experts mondiaux dans le domaine de la biologie du vieillissement, de la signalisation cellulaire, du métabolisme, de l’épigénétique, des cellules souches, du rythme circadien, de la démographie humaine et des maladies métaboliques, offrant ainsi une approche interdisciplinaire unique à la question du vieillissement. Les participants formaient un groupe varié, avec huit scientifiques venant d’Europe et dix des Etats-Unis, incluant cinq scientifiques juniors. Plusieurs thèmes intéressants ont émergé au cours du séminaire, notamment le contrôle centralisé du métabolisme et du vieillissement par le système nerveux, l’importance de la détection des nutriments pour les conditions normales et pathologiques, la régulation des mécanismes du vieillissement dans différents organes (cerveau, intestin, et gonades), et les effets sur les générations futures. Le séminaire a également mis en exergue l’importance de la régulation des cellules souches pendant le vieillissement, révélant le rôle intégratif de la régulation transcriptionnelle, de l’homéostase des protéines, et du métabolisme dans la quiescence et l’activation des cellules souche ainsi que les moyens par lesquelles ces connaissances pourraient être exploitées pour la régénération des tissus au cours du vieillissement.

Summary

This seminar brought together world experts in biology of ageing, cell signalling, metabolism, epigenetics, stem cells, circadian rhythms, human demography and metabolic disease, providing a unique interdisciplinary approach to ageing. The participants were diverse, with eight scientists from Europe and ten from the United States, including five junior scientists. Several exciting themes emerged during the seminar, notably the central control of metabolism and aging by the nervous system, the importance of nutrient sensing in health and diseases, the regulation of ageing pathways in different organs (brain, gut, and gonads), and the effects on the next generations. The seminar also highlighted the importance of stem cell regulation during the ageing process, underscoring the integrative roles of transcriptional regulation, protein homeostasis, and metabolism in stem cell quiescence and activation, and the ways in which this knowledge could be exploited for tissue regeneration during ageing.

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Compte-rendu

A major theme that emerged from the seminar was the central control of ageing and fat metabolism by the nervous system. Obesity is a major health risk, particularly during ageing, and an understanding of the behavioural processes that lead to the condition is essential for its prevention. Speaker Bruening outlined how evidence is growing for the crucial importance of the central nervous system in detection of nutrients and control of metabolism, and how these adaptive physiological mechanisms are overwhelmed and lead to pathology in obesity. Mair emphasized the dominance of the central nervous system over the periphery, with signalling mechanisms that protect against high-fat intake effective when activated only in neurons, through monoamine signalling. The important role of sensory perception in organismal ageing was also shown by Dillin, who explored the importance of perception of pain and smell. Reddy illustrated the fundamental importance of circadian rhythms for metabolism, with roles both for central neural clocks and for redox reactions within cells, which can generate autonomous rhythms. These circadian rhythms affect both vulnerability to disease events, such as heart attack, and also the metabolic consequences of eating at different time of day. These findings are shifting attention to include both cell autonomous events and the key role of neural control of metabolism in health and disease.

The key role played by nutrient-sensing pathways in health and diseases also emerged as a major theme of the seminar. mTOR signalling is a cell-autonomous part of this signalling network. Sabatini described recent work discovering how mTOR activity is regulated by specific amino acids, with the integration of multiple, parallel, molecular pathways and mechanisms. Slagboom discussed the evidence from human studies of ageing, and the ways in which different genetic variants are important in health during different age classes. She presented how nutrient-sensing networks are important, as are thyroid activity, blood pressure, and somatic mutations in epigenetic regulators. Several talks highlighted the importance of precise understanding of mechanisms of cell signalling for tackling ageing-related diseases, particularly cancer and neurodegeneration. Hall and Alessi discussed the importance of SGK3 and mTORC2 in resistance to cancer chemotherapy, and Alessi also revealed an important role of ubiquitination for mediating the effect of PINK 1 in Parkinson’s Disease. Kennedy discussed the precise constellation of genetic and signalling changes that give can rise to health during ageing, with an emphasis on the action of components of the mTOR signalling network. The implications for the use of drugs to improve health during ageing was also elaborated by Partridge for the Ras pathway. A general message to emerge from these discussions was the importance of multiple parallel molecular mechanisms in the progression of disease states, and therefore the need in therapy to both interfere with more than one mechanisms, and with different mechanisms depending upon the state of disease progression.

Several talks discussed the two-way interaction between the germline and soma in ageing, and the role of epigenetic memory of metabolic events across generations. Kenyon presented new data on the importance of fertilization in rejuvenating several hallmarks of aging. Aguilaniu outlined the key role played by signalling from the germline in somatic ageing, and how fat metabolism was impacted by fertility. Hansen developed the evidence for the importance of regulation of autophagy, a cellular process central for metabolism and homeostasis, in organismal ageing, in different tissues, and reported interplay with another homeostatic system, the heat-shock response. Bodmer described the highly toxic effects of a high fat diet on cardiac function, and how the effects of high fat feeding on heart dysfunction can persist for 3 generations, and the protective effect of patterns of histone methylation. Pospisilik showed that sugar feeding during spermatogenesis led to an open chromatin state and obesity in offspring, and the crucial role of Trim28 in sensitizing epigenetically-driven obesity state, molecular events that appear also active in obese children.

Finally, the seminar also highlighted the importance of stem cell regulation during the ageing process, with several aspects of stem cell biology being discussed. Jasper spoke about stem cells in the intestine, and the key roles of the gut microbiome in producing gut dysfunction during ageing, and the importance of transcriptional regulation of proteostasis, of metabolism and of calcium signalling in quiescence and activation, and the ways in which this knowledge could be exploited for tissue regeneration. Rando analysed the reasons for the impaired activation of stem cells in ageing tissues such as muscle, and described the phenomenon and molecular mechanisms of stem cell priming, where tissue injury can act at a distance to alert stem cells that then activate more readily in response to an injury. Brunet described a new method for isolation of ageing neural stem cells, and discussed the changes in gene expression that occur during quiescence, activation and ageing, particularly to markers of autophagy and proteostasis. General messages to emerge from these talks were the highly dynamic states of stem cells and the key role of metabolic signalling for their function.